1. Field of the Invention
The present invention relates to pharmaceuticals, and particularly to benzo[d]imidazole derivatives of piperidine and piperazine useful for the treatment of schizophrenia.
2. Description of the Related Art
Schizophrenia is a devastating psychiatric illness afflicting 1% of the population worldwide. The diagnosis of disease is based on diverse and variably expressed symptoms that can be grouped as positive and negative. The positive symptoms include disorganized thought, delusions, and auditory hallucinations while negative symptoms are emotional flattening, poverty of speech and motivational deficits. The first-generation antipsychotics, such as chlorpromazine 1 and haloperidol 2a, are dopamine antagonists and exhibit robust control of positive symptoms, such as hallucinations, agitation and delusions, but fail to control the negative symptoms, for instance, blunted affect, emotional withdrawal and cognitive deficits.

In addition, selective D2 receptor antagonists lead to extrapyramidal symptoms (EPS), such as dystonia and dyskinesia, and hyperprolactinemia. With respect to classical neuroleptics, the ‘second-generation’ or atypical antipsychotics, such as clozapine 2b, show significantly greater efficacy, including an improved effect on negative symptoms, and causes a marked increase in dopamine output in the prefrontal cortex

Clozapine 2b exhibits partial agonist efficacy for 5-HT1A receptor-mediated stimulation of G-protein activation, which accounts for part of the activity of clozapine in a model of anxiolytic-like activity, namely, clozapine inhibited stress-induced ultrasonic vocalization in rats, an effect attenuated by selective 5-HT1A antagonist WAY-100635. With respect to first generation antipsychotics, clozapine 2b shows significantly greater efficacy, including an improved effect on negative symptoms, and causes a marked increase in dopamine output in the prefrontal cortex. However, clozapine is implicated in a set of serious side effects, such as weight gain, diabetes and an increased risk of seizures and agranulocytosis.
Although the utility of 5-HT1A receptor agonism in the treatment of schizophrenia is clearly evident, the optimal level of activation of this target is debatable. To achieve improved overall therapeutic benefit, combining D2 receptor antagonism with 5-HT1A receptor agonism, rather than antagonism, has attracted a great deal of interest recently. Several mechanistic considerations and preclinical evidence have supported the potential of such a combination. As a result, adoprazine 3 (SLV-313) and bifeprunox 4, which are potent D2 receptor antagonists and 5-HT1A receptor agonists, were developed.


The antipsychotic efficacy of bifeprunox 4 was determined to be inferior to that of risperidone and olanzapine, and despite a satisfactory tolerance profile, the FDA did not grant marketing approval. The lack of sufficient antipsychotic efficacy of bifeprunox 4 likely reflects its marked agonism at D2 receptors. Thus, bifeprunox 4 suppresses basal firing rates of dopaminergic neurons in the ventral tegmental area and elicits circling behavior in rats unilaterally lesioned with 6-OH-DA. In addition, the failure of adoprazine 3 and bifeprunox 4 to oppose phencyclidine-induced social interaction deficits suggested that an appropriate ‘balance’ of activity at these sites is necessary for activity in this model. Therefore, there is a need to discover new chemical entities bearing varying ratios of D2 and 5-HT1A activities.
Thus, benzo[d]imidazole derivatives of piperidine and piperazine solving the aforementioned problems are desired.